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Clinical Cancer Research Vol. 6, 1796-1803, May 2000
© 2000 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Expression and Prognostic Significance of IAP-Family Genes in Human Cancers and Myeloid Leukemias1

Ingo Tamm2, Steven M. Kornblau, Harry Segall, Stanislaw Krajewski, Kate Welsh, Shinichi Kitada, Dominic A. Scudiero, Gabriela Tudor, Yi Hua Qui, Anne Monks, Michael Andreeff and John C. Reed3

The Burnham Institute, La Jolla, California 92037 [I. T., S. K., K. W., S. K., J. C. R.]; University of Texas, M. D. Anderson Cancer Center, Houston, Texas 77030 [S. M. K., H. S., Y. H. Q., M. A.]; and National Cancer Institute, Developmental Therapeutics Program, Frederick Cancer Research and Development Center, Frederick, Maryland [D. A. S., G. T., A. M.]

Expression of several inhibitor of apoptosis proteins (IAPs) was investigated in the National Cancer Institute panel of 60 human tumor cell lines, and the expression and prognostic significance of one of these, XIAP, was evaluated in 78 previously untreated patients with acute myelogenous leukemia (AML). XIAP and cIAP1 were expressed in most cancer lines analyzed, with substantial variability in their relative levels. In contrast, NAIP mRNA was not detectable, and cIAP2 was found at the mRNA and protein levels in only 34 (56%) and 5 (8%) of the 60 tumor cell lines analyzed, respectively. Interestingly, XIAP, cIAP1, and cIAP2 mRNA levels did not correlate with protein levels in the tumor lines, indicating posttranscriptional regulation of expression. High levels of XIAP protein in tumor cell lines were unexpectedly correlated with sensitivity to some anticancer drugs, particularly cytarabine and other nucleosides, whereas higher levels of cIAP1 protein levels were associated with resistance to several anticancer drugs. The relevance of XIAP to in vivo responses to cytarabine was explored in AML, making correlations with patient outcome (n = 78). Patients with lower levels of XIAP protein had significantly longer survival (median, 133 versus 52.5 weeks; P = 0.05) and a tendency toward longer remission duration (median, 87 versus 52.5 weeks; P = 0.13) than those with higher levels of XIAP. Altogether, these findings show that IAPs are widely but differentially expressed in human cancers and leukemias and suggest that higher XIAP protein levels may have adverse prognostic significance for patients with AML.




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